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PERSPECTIVES IN PHARMACOLOGY
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan
Received March 12, 2007; accepted July 31, 2007.
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Abstract |
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In 1937 in Italy, Erspamer and Vially observed that a substance derived from the enterochromaffin cells of the gut caused smooth muscle contraction, especially in the rat uterus. This substance was called enteramine. In 1948 in the United States, M. M. Rapport, A. A. Green, and I. H. Page (Rapport et al., 1948) isolated a compound from beef serum that was able to cause vascular contraction, which they called serotonin. Some years later, enteramine and serotonin were found to be the same substance: 5-hydroxytryptamine (5-HT). The recognition of 5-HT as a neurotransmitter after it was found in mammalian brain brought it into the field of neuroscience. These findings were followed by the proposed role of 5-HT in mental illness (for review, see Whitaker-Azmitia, 1999
). The involvement of 5-HT in the central nervous system has long been established and, therefore, is beyond the scope of this review.
Despite initially being described as a vasoconstrictor, the role of 5-HT in the cardiovascular system is far from being elucidated. A role for 5-HT in the pulmonary circulation has become established in the last past decade. However, sites of 5-HT synthesis in the nonpulmonary peripheral vasculature have not yet been identified. As a consequence, our current understanding is that the systemic vasculature is exposed to 5-HT only through the release of 5-HT by the platelet. In the peripheral circulation, whereas the function of 5-HT in the blood is to promote platelet aggregation and blood clotting, the role of 5-HT in the peripheral vasculature has not yet been clarified and is, to be more precise, controversial (Watts, 2005).
The circulatory system consists of arteries and veins. However, studies in veins occupy only a marginal part of the total research in the cardiovascular field compared with arteries. Paradoxically, venous diseases have been recognized since old times as mentioned by Hippocrates (460–377 B.C.), and they currently affect 1 to 3% of the population.
A number of cardiovascular diseases involve alterations in the synthesis of vasoactive hormones. Understanding the pharmacological and physiological function and regulation of these systems is of extreme value to understanding the pathophysiology and treatment of these diseases. The pharmacology of 5-HT in the peripheral vascular system, with focus on the venous system, is the main thrust of this review. Within this article, the pharmacological manipulation of the serotonergic system from its synthesis to degradation to mechanism of action is discussed. An introduction of the venous system as an important target for drugs that interfere with the serotonergic system is also presented.
The following topics covered in this article are 5-HT receptors in the vascular system; neuronal regulation of vascular tone by 5-HT; contractile synergism; role of veins in the cardiovascular system; 5-HT receptor-independent effects; 5-HT synthesis, storage, metabolism, uptake, and release; venous diseases; and 5-HT in veins.
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5-HT Receptors in the Vascular System |
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). The present classification establishes that the physiological actions of 5-HT are mediated by seven families of 5-HT receptors (5-HT1–5-HT7), with at least 15 different subtypes (Hoyer et al., 1994).
Most of 5-HT receptors belong to the family of seven-transmembrane domain receptors coupled to G-proteins. The only exception is the 5-HT3 receptor, which is a ligand-gated ion channel. With so many receptors, the complexity of 5-HT biological responses is not surprising. For example, whereas in porcine vena cava, 5-HT induces relaxation (Trevethick et al., 1984), in rabbit vena cava it elicits weak contraction (Hellegouarch et al., 1985). In rat vena cava, we observed that 5-HT induced approximately 70% of the magnitude of contraction induced by the adrenergic agonist norepinephrine (Fig. 1A).
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). Figure 1 compares the contraction induced by 5-HT in rat vena cava (Fig. 1, A and C) and rat aorta (Fig. 1, B and D), revealing differences between arteries and veins.
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5-HT1 Receptors: 5-HT1B, 5-HT1D, and 5-HT1F |
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In veins, 5-HT1 receptor activation generally leads to contraction, whereas arteries respond quite differently. For instance, the 5-HT1B agonist CP93129 failed to induce contraction in rat aorta, although the 5-HT1B receptor was expressed (Banes and Watts, 2003). On the other hand, we observed that CP93129 and sumatriptan induced contraction of rat mesenteric artery from hypertensive but not from normotensive rats (Banes and Watts, 2001).
It is interesting that the presence of 5-HT1F mRNA has been detected in several blood vessels, including human cerebral and coronary arteries (Watts and Cohen, 1999). However, selective 5-HT1F agonists, such as LY344864, failed to induce contraction in these arteries (Bouchelet et al., 2000). LY344864 did not induce contraction of mesenteric artery (Watts, 2002) or rabbit saphenous vein (Cohen and Schenk, 2000). On the other hand, 5-HT1F was not found in rat aorta and in rat vena cava (Ullmer et al., 1995). These data suggest that the 5-HT1F receptor does not mediate contractions in vascular tissues.
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5-HT2: 5-HT2A and 5-HT2B |
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). As mentioned above, the 5-HT2A receptor subtype is the primary receptor activated by 5-HT to induce contraction in arteries such as aorta (McKune and Watts, 2001). The 5-HT2A receptor agonist 
-methyl-5-HT caused contraction of rat tail artery (Froldi et al., 2003). Both 5-HT2A and 5-HT2B receptors are expressed and mediate contraction in rat renal artery (Watts and Thompson, 2004). On the other hand, the 5-HT2B receptor is the primary contractile receptor in the aorta, whereas the 5-HT2A receptor remains the primary contractile receptor in the mesenteric resistance arteries of hypertensive rats (Watts, 2002).
5-HT2B receptors are reported to mediate endothelium-dependent relaxation in porcine vena cava and pulmonary artery, as well as rabbit and rat jugular vein (for review, Watts and Cohen, 1999). However, unpublished data from our laboratory failed to show vasodilation induced by 5-HT in rat aorta, rat mesenteric artery, rat mesenteric resistance artery, and mouse aorta with intact endothelium.
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5-HT7 |
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). However, in unpublished data from our laboratory, we have been unable to observe relaxation induced by 5-HT in isolated blood vessels, including aorta. These data suggest that 5-HT7 receptor activation in these vessels does not mediate relaxation. There is evidence of 5-HT7 receptor mediating relaxation of canine coronary artery. The 5-HT7 receptor antagonist LY215840 inhibits 5-HT-induced relaxation of canine coronary artery (Watts and Cohen, 1999). To our knowledge, 5-HT-induced relaxation of rat vena cava has not been reported. |
Neuronal Regulation of Vascular Tone by 5-HT |
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). On the other hand, Cohen et al. (1999) reported that, in the rabbit saphenous vein, 5-HT enhances the release of norepinephrine by stimulating prejunctional 5-HT1A receptors on the noradrenergic nerves. These data indicate that 5-HT may also regulate vascular smooth muscle tone by modulating the sympathetic neurotransmission in blood vessels in a complex way. |
Contractile Synergism |
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). 5-HT can also interact synergistically with other vasoconstrictors, including angiotensin II, endothelin-1, histamine, and prostaglandin F2 (Watts, 2000). The reverse—potentiation of 5-HT effects by other hormones—is also true. Neuropeptide Y potentiates 5-HT-induced contraction in porcine coronary artery, and 5-HT sensitivity is increased by phenylephrine in rabbit femoral artery (Tsurumaki et al., 2006). In rabbit saphenous vein, histamine and the thromboxane A2 agonist increased the potency and efficacy of the 5-HT1B/1D agonist sumatriptan, an effect that was not observed in basilar artery (Bhattacharya et al., 2003). From this glimpse at 5-HT receptor pharmacology in arteries and veins, we can observe the complex effects resulting from 5-HT receptor activation. 5-HT activates distinct receptor subtypes in arteries and veins, which may underlie the different contributions of these vessels to vascular homeostasis. Compared with the arterial system, the role of the venous system in the control of vascular homeostasis is significantly less studied and elucidated and, therefore, deserves our attention.
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Role of Veins in the Cardiovascular System |
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). Factors that determine blood pressure include total peripheral resistance determined by arterial tone and cardiac output, the volume of blood pumped out of the heart per minute. This means that blood pressure can be controlled by blood volume and by vasoconstriction. The mechanisms by which arterial smooth muscle tone and structure affect blood pressure have been extensively studied, whereas venous contribution has been relatively neglected. A majority (60–70%) of the circulating blood volume is in the veins at any given time, indicating that veins can modulate cardiovascular homeostasis.
The tunica media of a blood vessel is responsible for the control of vasomotor tone by contracting and relaxing to different stimuli. Compared with arteries, veins express considerably less -actin, the key protein for contraction. Given the thinner smooth muscle layer and decreased -actin expression in veins compared with arteries, one could postulate that veins do not contribute to cardiovascular homeostasis. However, based on all the previous information, there is strong evidence that veins do contract to agonists, including 5-HT. Moreover 5-HT can modulate the sympathetic system and/or interact synergistically with other systems in veins. Altogether, these data highlight the importance of studying the serotonergic system in veins.
Venous tone can be estimated in vivo by measuring mean circulatory filling pressure, which is determined by venous capacitance and blood volume. Venous capacitance is a measure of venous compliance or the state of venous contractility.
In some models of hypertension, total blood volume is not increased, despite an increase in mean circulatory filling pressure, suggesting that mean circulatory filling pressure is driven exclusively by changes in venous tone. Upon a decrease in venous return, as it occurs following a change in posture from supine to the upright position, cardiac output and blood pressure decrease. The low blood pressure reduces afferent nerve firing from the arterial baroreceptors, and this increases sympathetic firing to resistance, as well as capacitance vessels. Increased venous sympathetic nerve activity causes the constriction of the venous smooth muscle, which reduces venous capacity to increase venous return. For this reason, venomotor tone can be modulated by drugs that interfere with the sympathetic nerve activity. Body venous tone is also altered in various physiological and pathophysiological conditions, such as diabetes mellitus, hypertension, mental stress, aging, and autonomic dysfunction, to name a few (for review, Pang, 2001). Altogether, these data support the concept that veins actively participate in the regulation of vascular tone.
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5-HT Receptor-Independent Effects |
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). A receptor-independent response to 5-HT involving 5-HT transamidation to small GTPases has been reported in platelets (Walther et al., 2003). These data indicate that, once inside the cell, the effects of 5-HT are not extinguished. However, 5-HT synthesis in platelets and blood vessels has not been reported to date, indicating that the intracellular 5-HT is coming from the extracellular media. What then is the mechanism for 5-HT uptake by the vascular cell? An excellent candidate is the 5-HT transporter (SERT) as inhibition of SERT inhibits pulmonary arterial cell proliferation (Marcos et al., 2003). In the next section of this review, 5-HT biochemistry is discussed with emphasis in 5-HT uptake via SERT. |
5-HT: From Synthesis to Metabolism |
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Synthesis |
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TPH |
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).
In idiopathic pulmonary arterial hypertension, the endothelium expresses increased TPH-1 gene (Eddahibi et al., 2006). TPH-1 and peripheral 5-HT play an essential role in the development of hypoxia-induced elevation in pulmonary pressures and pulmonary vascular remodeling (Morecroft et al., 2007). Inhibition of 5-HT synthesis by blocking TPH with p-chlorophenylalanine methyl ester reduces the hyperplasia of the pulmonary arterial smooth muscle (Eddahibi et al., 2006).
In saphenous vein, Cohen et al. (1999) observed that 5-HT concentration is reduced by the TPH inhibitor p-chlorophenylalanine methyl ester (Cohen et al., 1999), suggesting 5-HT synthesis in the peripheral vasculature. However, it is important to note that the saphenous vein is richly innervated and that neuronal 5-HT synthesis may account for the measured 5-HT. Preliminary data from our laboratory show TPH-1 gene expression in rat aorta (cycle threshold values for TPH-1 and the housekeeping gene 
-2-microglobulin, respectively: 28.77 ± 0.33 cycles and 17.24 ± 0.09 cycles). The relatively poor innervation of rat aorta supports the presence of the enzyme in smooth muscle or endothelium cells. However, TPH activity in blood vessels requires further investigation.
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AADC |
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), suggesting the importance of 5-HT synthesis by AADC to these responses. We have previously observed that treatment of animals with the AADC inhibitor NSD 1015 did not reveal the 5-HT precursor in rat aorta (Ni et al., 2004). These results suggest that it is unlikely that arteries synthesize 5-HT. However, the possibility that 5-HTP may leave the cell, becoming unavailable for measurements, can not be excluded. This possibility is further supported by preliminary data from our laboratory indicating both 5-HTP uptake and the presence of AADC in rat aorta. Whereas the enzymatic inhibitors would lead to decreased levels of 5-HT, increased administration of the 5-HT precursors tryptophan and 5-HTP can increase 5-HT synthesis. Increased contraction to acetylcholine was observed in mouse duodenum after tryptophan administration due to 5-HT synthesis. However, whereas 5-HTP induces contraction in cerebral vessels, it failed to induce contraction of femoral arteries.
Here we present evidence that the peripheral blood vessels may function as possible sites of 5-HT synthesis, and this information is new with respect to veins. Further studies are ultimately needed to fill the gap in this area.
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Storage |
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Different forms of 5-HT storage may exist, as suggested by the findings in enterochromaffin cells, showing that a small part of 5-HT remains outside the secretory granules. 5-HT could also be covalently bound to proteins that are to be stored in platelets (Walther et al., 2003).
We reported the presence of 5-HT in aorta (Ni et al., 2004). 5-HT content in saphenous vein has been measured previously (Cohen et al., 1999). Preliminary data from our laboratory reveal the presence of basal levels of 5-HT in veins in higher amounts than that observed in arteries (Fig. 2). However, whether and how 5-HT is stored in aorta and in veins have yet to be proven.
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Metabolism |
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MAO activity is measurable in rat aorta. For example, we observed increased levels of 5-HT simultaneously with blunted levels of 5-HIAA in aorta and carotid and superior mesenteric arteries from pargyline-treated rats (Ni et al., 2004). Cohen et al. (1999) found that pargyline treatment increased the amount of 5-HT measured in saphenous vein, indicating the presence of this enzyme in this tissue (Cohen et al., 1999). Altogether, these data suggest that the peripheral vasculature has the ability to metabolize 5-HT and may, therefore, be an important site for the serotonergic system.
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Uptake and Release of 5-HT |
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SERT is widely distributed in the central nervous system and a target of antidepressant drugs, such as fluoxetine, fluvoxamine, citalopram, and paroxetine, and the anorexigen (+)-fenfluramine. Whereas fluoxetine inhibits SERT, (+)-fenfluramine is a SERT substrate and potent 5-HT releaser. SERT is also found in the peripheral sympathetic nervous system, as well as in platelets, gastrointestinal system, and lung.
SERT abnormalities are strongly associated with pulmonary hypertension. The classic concept that 5-HT function is terminated once inside the cell has been challenged by the findings that intracellular 5-HT mediates pulmonary arterial smooth muscle proliferation after uptake by SERT (Marcos et al., 2003).
After observing 5-HT immunostaining in rat aorta, we investigated the serotonergic system in peripheral arteries. Arteries exposed to extracellular 5-HT were capable of concentrating 5-HT. Moreover, this increase in arterial 5-HT levels was inhibited by the SERT inhibitor fluoxetine. A functional SERT in the rat peripheral arteries exists and SERT inhibition potentiates 5-HT-induced contraction (Ni et al., 2004). These findings opened a new avenue toward the understanding of the effects of local 5-HT in the peripheral vasculature. Most interestingly, we observed that, whenever exposed to exogenous 5-HT, vena cava is more likely to uptake larger amounts of 5-HT than aorta (Fig. 2). However, whether SERT is involved in 5-HT uptake in veins remains unsolved.
In light of the obvious differences between veins and arteries, it becomes clear that studies involving the venous system are of extreme importance in understanding whether these differences may influence the physiology and the pathophysiology of the cardiovascular system.
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Venous Diseases |
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). Deep venous thrombosis is strongly associated with an imbalanced activation of the coagulation system. Platelets play a key role not only in hemostasis but also in thrombogenesis. The beginning of the formation of an intravascular thrombus involves the adhesion of blood platelets to the damaged blood vessel, having the von Willebrand factor as the trigger for platelets to adhere to the subendothelium (for review, Jackson et al., 2003). 5-HT enhances von Willebrand factor secretion from endothelial cells in vitro (Palmer et al., 1994). However, it is not clear whether 5-HT can induce von Willebrand factor secretion in platelets. 5-HT increases procoagulant activity and reduces fibrinolytic activity of endothelial cells via 5-HT2A receptor activation, contributing to thrombus formation (Kawano et al., 2001). Whether the high amount of 5-HT found in veins contribute to the coagulation system remains to be investigated.
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5-HT in Veins |
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Conclusion |
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Footnotes |
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We apologize for not citing many important references that have contributed to this review due to space limitations.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: 5-HT, 5-hydroxytryptamine, serotonin; BRL 56905, (±)-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole; CP93129, 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one; GR127935, 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide; SERT, 5-HT transporter; LY215840, cis-n-(2-hydroxycyclopentyl)-6-methyl-1-(1-methylethyl)ergoline-8-carboxamide; LY344864, 4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]-benzamide; Ro 4-4602, DL-serine 2-(2,3,4-trihydroxybenzyl)hydrazide; SKF 99101H, (3-(2-dimethylaminoethyl)-4-chloro-5-proxyindole hemifumarate; TPH, tryptophan hydroxylase; 5-HTP, 5-hydroxytryptophan; AADC, amino acid decarboxylase; NSD 1015, 3-hydroxybenzylhydrazine; MAO, monoamine oxidase; 5-HIAA, 5-hydroxyindole acetic acid.
Address correspondence to. A. Elizabeth Linder, Department of Pharmacology and Toxicology, Michigan State University, B445 Life Sciences Building, East Lansing, MI 48824. E-mail: linderau{at}msu.edu
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Abstract
5-HT Receptors in the...
) or 1 µM of exogenous 5-HT (
) for 15 min. Blood vessel segments were isolated from pargyline-treated rats [to inhibit MAO and increase the measurable amount of 5-HT in rat aorta, as previously reported (Ni et al., 2004